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Stroke is one of the leading causes of long-term disability. Cell transplantation is a promising strategy to treat stroke. We explored the efficacy of directly reprogrammed human neural precursor cell (drNPC) transplants to promote functional recovery in a model of focal ischemic stroke in the mouse sensorimotor cortex. We show that drNPCs express neural precursor cell markers and are neurally committed at the time of transplantation. Mice that received drNPC transplants recovered motor function, irrespective of transplant vehicle or recipient sex, and with no correlation to lesion volume or glial scarring. The majority of drNPCs found in vivo, at the time of functional recovery, remained undifferentiated. Notably, no correlation between functional recovery and long-term xenograft survival was observed, indicating that drNPCs provide therapeutic benefits beyond their survival. Furthermore, increased synaptophysin expression in transplanted brains suggests that drNPCs promote neuroplasticity through enhanced synaptogenesis. Our findings provide insight into the mechanistic underpinnings of drNPC-mediated recovery for stroke and support the notion that drNPCs may have clinical applications for stroke therapy. [ABSTRACT FROM AUTHOR]

Since the original isolation of neural stem cells (NSCs) in the adult mammalian brain, further work has revealed a heterogeneity in the NSC pool. Our previous work characterized a distinct, Oct4 expressing, NSC population in the periventricular region, through development and into adulthood. We hypothesized that this population is upstream in lineage to the more abundant, well documented, GFAP expressing NSC. Herein, we show that Oct4 expressing NSCs give rise to neurons, astrocytes and oligodendrocytes throughout the developing brain. Further, transgenic inducible mouse models demonstrate that the rare Oct4 expressing NSCs undergo asymmetric divisions to give rise to GFAP expressing NSCs in naïve and injured brains. This lineage relationship between distinct NSC pools contributes significantly to an understanding of neural development, the NSC lineage in vivo and has implications for neural repair. [ABSTRACT FROM AUTHOR]

Neural stem cells and their progeny reside in two distinct neurogenic niches within the mammalian brain: the subventricular zone and the dentate gyrus. The interplay between the neural stem cells and the niche in which they reside can have significant effects on cell kinetics and neurogenesis. A comprehensive understanding of the changes to the niche that occur through postnatal development and aging, as well as following injury, is relevant for developing therapeutics and interventions to promote neural repair. We discuss changes that occur within the neural stem and progenitor cell populations, the vasculature, extracellular matrix, microglia, and secreted proteins through aging which impact cell behavior within the neurogenic niches. We examine neural precursor cell and niche responses to injury in neonatal hypoxia-ischemia, juvenile cranial irradiation, and adult stroke. This review examines the interplay between the niche and stem cell behavior through aging and following injury as a means to understand intrinsic and extrinsic factors that regulate neurogenesis in vivo. [ABSTRACT FROM AUTHOR]

Stem cell-based therapies for the treatment of stroke have received considerable attention. Two broad approaches to stem cell-based therapies have been taken: the transplantation of exogenous stem cells, and the activation of endogenous neural stem and progenitor cells (together termed neural precursors). Studies examining the transplantation of exogenous cells have demonstrated that neural stem and progenitor cells lead to the most clinically promising results. Endogenous activation of neural precursors has also been explored based on the fact that resident precursor cells have the inherent capacity to proliferate, migrate and differentiate into mature neurons in the uninjured adult brain. Studies have revealed that these neural precursor cell behaviours can be activated following stroke, whereby neural precursors will expand in number, migrate to the infarct site and differentiate into neurons. However, this innate response is insufficient to lead to functional recovery, making it necessary to enhance the activation of endogenous precursors to promote tissue repair and functional recovery. Herein we will discuss the current state of the stem cell-based approaches with a focus on endogenous repair to treat the stroke injured brain. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) protein-patterned scaffolds provide a more biomimetic environment for cell culture than traditional two-dimensional surfaces, but simultaneous 3D protein patterning has proved difficult. We developed a method to spatially control the immobilization of different growth factors in distinct volumes in 3D hydrogels, and to specifically guide differentiation of stem/progenitor cells therein. Stem-cell differentiation factors sonic hedgehog (SHH) and ciliary neurotrophic factor (CNTF) were simultaneously immobilized using orthogonal physical binding pairs, barnase-barstar and streptavidin-biotin, respectively. Barnase and streptavidin were sequentially immobilized using two-photon chemistry for subsequent concurrent complexation with fusion proteins barstar-SHH and biotin-CNTF, resulting in bioactive 3D patterned hydrogels. The technique should be broadly applicable to the patterning of a wide range of proteins. [ABSTRACT FROM AUTHOR]

The concept of stem-cell plasticity received strong support from a recent observation that extensively passaged, clonally derived neural stem cells could contribute to hematopoiesis. We investigated whether hematopoietic potential was a consistent or unusual feature of neural stem cells, and whether it depended on the extent of in vitro passaging before transplantation. Here we transplanted over 128 × 106 neurosphere cells into 128 host animals; however, we never observed contribution to hematopoiesis, irrespective of the number of passages and despite the use of an assay that could detect the contribution of a single blood stem cell to hematopoietic repopulation. Although extensively cultured neurosphere cells continued to generate neural progeny, marked changes in their growth properties occurred, including changes in growth-factor dependence, cell-cycle kinetics, cell adhesion and gene expression. Our results exclude hematopoietic competence as a consistent property of intravenously infused neural stem cells. However, the consistent changes that occurred during extended passaging are compatible with genetic or epigenetic alterations and suggest that rare transformation events may account for the neural-to-blood fate switch originally reported. [ABSTRACT FROM AUTHOR]

Presents reply of Cindi M. Morshead et al. to questions and concerns raised by other scientific groups on findings of their study conducted on neural stem cell properties. Emphasis on conducting studies to examine transdifferentiation potential of cells using colonally derived neural stem cells; Explanation for failure to replicate hematopoietic transdifferentiation in their study.